Neuromodulators and Circadian Clocks: Roles in Retinal Function and Dysfunction

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Project Summary / Abstract Circadian clocks generate daily biological rhythms that provide adaptive advantage to organisms by allowing them to anticipate and prepare for regular daily changes in their environment. Circadian disruption has been associated with numerous immune, inflammatory, and metabolic disorders, including diabetic retinopathy. The retina contains multiple circadian clocks located in a variety of retinal cell types, including amacrine, ganglion, photoreceptor, and retinal pigment epithelial (RPE) cells, that modulate visual processing and generate a circadian rhythm of protection from photo-oxidative stress. Circadian clocks are transcriptional-translational feedback loops of conserved clock genes and proteins that generate ~24h rhythms. CLOCK and NPAS2 have overlapping roles in the feedback loops and both regulate circadian gene transcription. The relative contributions of CLOCK and NPAS2 to retinal circadian oscillators have not been explored. In addition, the mechanisms whereby diverse retinal clocks are entrained to the light-dark cycle and are synchronized to regulate retinal function are still unclear. Dopamine (DA) is a circadian neuromodulator that optimizes retinal physiology for bright light, high-resolution vision during the daytime. We hypothesize that DA synchronizes circadian clocks expressing NPAS2 and CLOCK in distinct retinal cell types to modulate visual processing and rhythmic protection from photo-oxidative stress. Using established genetic models and novel mouse models in which DA and/or specific clock genes are depleted selectively from the retina by conditional gene disruption, we will examine circadian rhythms of visual function, sensitivity to photo-oxidative stress, and gene expression to provide a more clear understanding of the organization retinal circadian clock networks. Research proposed in this application is designed to test the following three predictions of our hypotheses: (1) DA modulates circadian rhythms of contrast sensitivity via dopamine D4 receptor (D4R)-mediated regulation of cAMP signaling and circadian oscillators that drive rhythms with both CLOCK/BMAL1 and NPAS2/BMAL1 complexes. (2) Circadian rhythms of photopic ERG amplitudes are modulated by DA effects on photoreceptors via D4Rs, cAMP, and oscillators that utilize CLOCK but not NPAS2. (3) DA protects photoreceptors against photo-oxidative stress via D4Rs on photoreceptors and via dopamine D5 receptors (D5Rs) and dopamine D2-like receptors on RPE cells by modulating a CLOCK-dependent circadian rhythm of susceptibility to light damage. These innovative studies will elucidate mechanisms of retinal circadian physiology that control high-resolution vision and sensitivity to photo-oxidative stress. They will provide novel insights into ways to improve visual function at night (e.g., shift workers, pilots) and to prevent or treat retinal degenerative diseases.